Synthesis, biological evaluation, and in silico study of novel library sulfonates containing quinazolin-4(3H)-one derivatives as potential aldose reductase inhibitors

Abstract

A series of novel sulfonates containing quinazolin-4(3H)-one ring derivatives was designed to inhibit aldose reductase (ALR2, EC 1.1.1.21). Novel quinazolinone derivatives (1–21) were synthesized from the reaction of sulfonated aldehydes with 3-amino-2-alkylquinazolin-4(3H)-ones in glacial acetic acid with good yields (85%– 94%). The structures of the novel molecules were characterized using IR, 1 H-NMR, 13C-NMR, and HRMS. All the novel quinazolinones (1–21) demonstrated nanomolar levels of inhibitory activity against ALR2 (KIs are in the range of 101.50– 2066.00 nM). Besides, 4-[(2-isopropyl-4-oxoquinazolin-3[4H]-ylimino)methyl]phenyl benzenesulfonate (15) showed higher inhibitor activity inhibited ALR2 up to 7.7-fold compared to epalrestat, a standard inhibitor. Binding interactions between ALR2 and quinazolinones have been investigated using Schrödinger Small-Molecule Drug Discovery Suite 2021–1, reported possible inhibitor-ALR2 interactions. Both in vitro and in silico study results suggest that these quinazolin-4(3H)-one ring derivatives (1–21) require further molecular modification to improve their drug nominee potency as an ALR2 inhibitor.